Preparation of 8-amido-2-dimethylamino-1,2,3,4-tetrahydro-2-dibenzofurans and several fluorinated derivatives via [3,3]-sigmatropic rearrangement of O-aryloximes

Article abstract of DOI:10.1021/jo020600b

Methodology to prepare 8-amido-2-amino-1,2,3,4-tetrahydro-2-dibenzofurans, analogues with a fluorine substituent incorporated in the 6-, 7-, and 9-positions, and a difluorinated analogue with fluorines in the 6- and 9-positions is described. The tetrahydrodibenzofuran ring systems are prepared by acid-catalyzed [3,3]-sigmatropic rearrangement of O-aryloximes. Regioselective reactions to prepare the requisite O-aryloxime intermediates from commercially available fluorobenzene derivatives are discussed.

Full text of DOI:10.1021/jo020600b

P r ep a r a tion of
8-Am id o-2-d im eth yla m in o-1,2,3,4-tetr a h yd r o-2-d iben zofu r a n s a n d
Sever a l F lu or in a ted Der iva tives via [3,3]-Sigm a tr op ic
Rea r r a n gem en t of O-Ar yloxim es
Peter R. Guzzo,*,† Ronald N. Buckle,† Ming Chou,† Sean R. Dinn,† Michael E. Flaugh,‡
Anton D. Kiefer, J r.,‡ Kendal T. Ryter,† Anthony J . Sampognaro,† Steven W. Tregay,† and
Yao-Chang Xu*,‡
Albany Molecular Research, Inc., 21 Corporate Circle, P.O. 15098, Albany, New York 12212-5098, and
Eli Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana 46285
peter@albmolecular.com; xu_yao_chang@lilly.com
Received September 12, 2002
Methodology to prepare 8-amido-2-amino-1,2,3,4-tetrahydro-2-dibenzofurans, analogues with a
fluorine substituent incorporated in the 6-, 7-, and 9-positions, and a difluorinated analogue with
fluorines in the 6- and 9-positions is described. The tetrahydrodibenzofuran ring systems are
prepared by acid-catalyzed [3,3]-sigmatropic rearrangement of O-aryloximes. Regioselective reactions
to prepare the requisite O-aryloxime intermediates from commercially available fluorobenzene
derivatives are discussed.
In tr od u ction
Serotonin (1, 5-hydroxytryptamine, 5-HT; Figure 1) is
a prominent neurotransmitter with diverse physiological
actions in both the central and peripheral nervous
systems. Seven families of serotonin receptors (5-HT1-
5-HT7) and 14 distinct serotonin receptor subtypes have
been identified in the mammalian central nervous sys-
tem.1 The identification of selective agonists and antago-
nists for the diverse serotonin receptor subtypes has been
an active area of investigation.
Serotonin 1F agonists have demonstrated potential for
the treatment of migraine headaches.2 Previously, tet-
rahydrocarbazole 2 (LY344864; Figure 1) was demon-
strated to be a potent and selective serotonin 1F receptor
agonist.2a In connection with a program to discover novel
and selective 5-HT1F agonists, tetrahydrodibenzofuran
analogues 3 were selected as targets.3 The synthesis of
F IGURE 1.
the parent tetrahydrodibenzofuran ring system as well
as syntheses to selectively incorporate fluorine atoms into
the 6-, 7-, and 9-positions and to create a difluorinated
analogue with fluorine atoms in the 6- and 9-positions
were explored. Herein the details for the syntheses of
these ring systems are described.
The incorporation of fluorine atoms into molecules
alters their physical and biological characteristics and
has been a popular strategy for studying structure
activity relationships in medicinal chemistry.4 Recently,
a series of fluorinated tryptamines has been prepared to
study the pharmacological effects of fluorination.5 In this
study, fluorine substitution at different positions around
* To whom correspondence should be addressed. Phone: 518-464-
0279. Fax: 518-464-0289 (P.G.). Phone: 317-277-2284. Fax: 317-277-
7035 (Y.-C.X.).
† Albany Molecular Research, Inc.
‡ Eli Lilly and Co.
(1) Hoyer, D.; Clarke, D. E.; Fozard, J . R.; Hartig, P. R.; Martin, G.
R.; Mylecharane, E. J .; Saxena, P. R.; Humphrey, P. P. A. Pharmacol.
Rev. 1994, 46, 157.
(2) (a) Phebus, L. A.; J ohnson, K. W.; Zgombick, J . M.; Gilbert, P.
J .; Van Belle, K.; Mancuso, V.; Nelson, D. L. G.; Calligaro, D. O.; Kiefer,
A. D.; Branchek, T. A.; Flaugh, M. E. Life Sci. 1997, 61, 2117. (b)
J ohnson, K. W.; Schaus, J . M.; Durkin, M. M.; Audia, J . E.; Kaldor, S.
W.; Flaugh, M. E.; Adham, N.; Zgombick, J . M.; Cohen, M. L.;
Branchek, T. A.; Phebus, L. A. Neuroreport 1997, 8, 2237. (c) Xu, Y.-
C.; J ohnson, K. W.; Phebus, L. A.; Cohen, M.; Nelson, D. L.; Schenck,
K.; Walker, C. D.; Fritz, J . E.; Kaldor, S. W.; LeTourneau, M. E.; Murff,
R. E.; Zgombick, J . M.; Calligaro, D. O.; Audia, J . E.; Schaus, J . M. J .
Med. Chem. 2001, 44, 4031.
(4) (a) Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; J ohn Wiley & Sons: New York, 1991. (b) Selective Fluori-
nation; Welch, J . T., Ed.; ACS Symposium Series 456; American
Chemical Society: Washington, DC, 1991. (c) Myers, A. G.; Barbay, J .
K.; Zhong, B. J . Am. Chem. Soc. 2001, 123, 7207.
(3) (a) Flaugh, M. E.; Kiefer, A. D. U.S. Patent 5,846,995, December
8, 1998. (b) Flaugh, M. E.; Kiefer, A. D. U.S. Patent 5,932,739, August
3, 1999.
10.1021/jo020600b CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/04/2003
770
J . Org. Chem. 2003, 68, 770-778

[3,3]-Sigmatropic Rearrangement of O-Aryloximes
SCHEME 1a
F IGURE 2.
the aromatic ring led to interesting changes in selectivity,
affinity, and functional activity at 5HT1A,2A,2C receptors
as well as differing behaviorial effects in animal models.
In a separate study, the synthesis of potential in vivo
precursors to fluorinated norepinephrines has been re-
ported.6 Access to several fluorinated tetrahydrodiben-
zofuran analogues 3 would allow for a systematic study
of the effects of ring fluorination on the binding selectivity
at serotonin receptors as well as effects on the metabo-
lism, distribution, and biological activity of the molecules.
One potential approach for the preparation of the
benzofuran derivatives of interest involves the acid-
catalyzed cyclization of O-aryloximes (Figure 2).7 The
transformation is analogous to the well-known Fischer
indole synthesis. A plausible reaction mechanism is
shown in Figure 2. The reaction proceeds through a [3,3]-
sigmatropic rearrangement followed by condensation to
form the benzofuran ring. On the basis of the proposed
mechanism, an electron-donating group substituted on
the aromatic ring would favor the [3,3]-sigmatropic
rearrangement. Conversely, electron-withdrawing sub-
stitution will inhibit the [3,3]-sigmatropic rearrangement
process. Limited literature reports seem to be consistent
with this mechanism.7 Our proposed targets, however,
have strong electron-withdrawing fluorine atom(s) on the
aromatic ring and fluorine substituents often can have
a strong impact on reactivity through complex electronic
effects.8 These fluorinated systems presented a major
hurdle for our effort in synthesizing these analogues.
These challenges, however, also provided us opportunities
to find new acid catalysts to promote the effective [3,3]-
sigmatropic rearrangement. In the end, this synthetic
approach proved well-suited to access the desired tet-
rahydrodibenzofuran derivatives (3) of interest to the
program.
a
(a) Me2NH in THF, CH2Cl2, Na(OAc)3BH, rt 18 h. (b) 6 M HCl,
reflux 1 h, 66% (2 steps). (c) NH2OH-HCl, EtOH, reflux 3 h, 87%.
(d) KH, 18-crown-6 (4 mol %), THF, 1-fluoro-4-nitrobenzene, 0 °C
to rt, 2 h, 90%. (e) 1 M HCl in acetic acid, 90-110 °C 7.5 h, 95%.
(f) 10% Pd/C, MeOH, H2, 12 h, 85%. (g) 4-Fluorobenzoyl chloride,
Et3N, THF, rt 16 h, 60%.
electron-withdrawing group or the use of a tricarbonyl-
chromium complex to activate aryl halides without the
presence of an electron-withdrawing group7h or (2) con-
densation of the aryloxyamine with the corresponding
ketone. The commercial availability of aryloxyamines is
quite limited, however. Substituted aryloxyamines can
be prepared by amination of the corresponding phenol,7g,9
copper-mediated cross-coupling with arylboronic acids
and N-hydroxyphthalimide,10 or through addition of
oximes to arylchromium complexes.11
Resu lts a n d Discu ssion
The synthetic approach to the parent 8-amido-2-amino-
1,2,3,4-tetrahydro-2-dibenzofuran scaffold is shown in
Scheme 1. Reductive amination of ketone 4 with di-
methylamine and sodium triacetoxyborohydride, followed
by acidic hydrolysis of the ketal, provided 4-dimethyl-
aminocyclohexanone in good yield. 4-Dimethylaminocy-
clohexanone was converted to oxime 5.12 Arylation of
oxime 5 with KH, catalytic 18-crown-6, and 1-fluoro-4-
nitrobenzene provided O-aryloxime 6 in good yield.
Cyclization of O-aryloxime 6 in 1.0 M hydrogen chloride
in acetic acid at reflux provided tetrahydrodibenzofuran
7 in 95% yield. The nitro group of 7 was reduced by
hydrogenation in the presence of palladium on carbon to
provide amine 8. Acylation of 8 with 4-fluorobenzoyl
chloride afforded amide 9, a tetrahydrodibenzofuran
analogue of LY344864 (2).13
The starting O-aryloximes are generally prepared by
the following two methods: (1) reaction of the anion of
an oxime and an aryl halide containing a suitable
(5) (a) Blair, J . B.; Kurrasch-Orbaugh, D.; Marona-Lewicka, D.;
Cumbay, M. G.; Watts, V. J .; Barker, E. L.; Nichols, D. E. J . Med.
Chem. 2000, 43, 4701. (b) Laban, U.; Kurrasch-Orbaugh, D.; Marona-
Lewicka, D.; Nichols, D. E. Bioorg. Med. Chem. Lett. 2001, 11, 793.
(6) Herbert, B.; Kim, I. H.; Kirk, K. L. J . Org. Chem. 2001, 66, 4892.
(7) (a) Sheradsky, T. Tetrahedron Lett. 1966, 5225. (b) Sheradsky,
T. J . Heterocycl. Chem. 1967, 4, 413. (c) Mooradian, A.; Dupont, P. E.
J . Heterocycl. Chem. 1967, 4, 441. (d) Mooradian, A. Tetrahedron Lett.
1967, 407. (e) Kaminsky, D.; Shavel, J .; Meltzer, R. I. Tetrahedron Lett.
1967, 859. (f) Mooradian, A.; Dupont, P. E. Tetrahedron Lett. 1967,
2867. (g) Castellino, A. J .; Rapoport, H. J . Org. Chem. 1984, 49, 4399.
(h) Alemagna, A.; Baldoli, C.; Buttero, P. D.; Licandro, E.; Maiorana,
S. Synthesis 1987, 192. (i) Liao, Y.; Kozikowski, A. P.; Guidotti, A.;
Costa, E. Bioorg. Med. Chem. Lett. 1998, 8, 2099.
(9) (a) Castellino, A. J .; Rapoport, H. J . Org. Chem. 1984, 49, 1348.
(b) Choong, I. C.; Ellman, J . A. J . Org. Chem. 1999, 64, 6528. (c) Foot,
O. F.; Knight. D. W. Chem. Commun. 2000, 975.
(10) Petrassi, H. M.; Sharpless, K. B.; Kelly, J . W. Org. Lett. 2001,
3, 139.
(11) Baldoli, C.; Buttero, P. D.; Licandro, E.; Maiorana, S. Synthesis
1988, 344.
(8) Schlosser, M. Angew. Chem., Int. Ed. Engl. 1998, 110, 1496.
J . Org. Chem, Vol. 68, No. 3, 2003 771

Guzzo et al.
SCHEME 2a
TABLE 1. Rea ction Con d ition s a n d Obser va tion s for
Con ver sion of 11 to 12
entry
conditions
yield/comment
1
2
3
4
5
6
7
8
1 M HCl/AcOH, reflux
formic acid, reflux, 1 h
trace product
trace product
trace product
no product
47%
14%
no product
25%
formic acid, 135 °C, sealed tube, 1 h
polyphosphoric acid, toluene, reflux
HCl (sat.)/AcOH, 140 °C, 1 h
10% H2SO4/ethanol, reflux, 2 h
10% H2SO4/water, reflux, 2 h
10% H2SO4/AcOH, reflux, 1 h
acetic acid (Entry 1), conditions that worked well for the
cyclization of desfluoro derivative 6, did not provide any
significant amount of desired product 12. Attempted
cyclization using both refluxing formic acid as well as
conducting the reaction in a sealed flask in formic acid
at 135 °C also did not provide a significant amount of 12
(entries 2 and 3). Refluxing with polyphosphoric acid in
toluene gave no product 12 (entry 4). The best conditions
found for this transformation were the use of acetic acid
saturated with HCl at 140 °C in a sealed flask (entry 5);
these conditions afforded a 47% yield of 12. All of
aryloxime 11 was consumed in the reaction and several
other byproducts from the reaction were not able to be
characterized. A few other conditions using sulfuric acid
were explored (entries 6-8) in an attempt to lower the
reaction temperature and avoid the use of a sealed flask.
The best results were achieved with sulfuric acid (10 vol
%) in acetic acid at reflux, which provided a 25% yield of
12. Hydrogenation of the nitro group of 12 with pal-
ladium on carbon followed by acylation with 4-fluoroben-
zoyl chloride provided the final amide 13.
Incorporation of fluorine substituents in the 7- and
9-positions of the 1,2,3,4-tetrahydrodibenzofuran ring
system was explored next. It was envisioned that both
derivatives could be prepared from a nonregioselective
cyclization of a common intermediate 3-fluoroaryloxime
derivative (see intermediates 15a -c, Scheme 3). Two
regioisomeric products can be envisioned in the reaction
of oxime 5 with difluorinated benzene compounds 14a -
c. Products derived from substitution of the 4-fluoro
substituent would provide the desired products 15a -c,
while substitution of the 2-fluoro substituent would
provide an undesired product 16a -c.
Arylation of oxime 5 with 2,4-difluoronitrobenzene
(14a ) using the reaction conditions of KH and 18-crown-6
gave a 3:97 ratio of 15a and 16a in favor of the undesired
regioisomer derived from displacement of the 2-fluoro
substituent (Scheme 3, Table 2). A literature report
describes the regioselective addition of potassium N-Boc-
4-piperidinoxide to the 4-position of 2,4-difluorobenzoni-
trile.15 However, in our case, arylation of the potassium
salt of oxime 5 with 2,4-difluorobenzonitrile (14b) re-
sulted in a 35:65 ratio of 15b and 16b, still in favor of
substitution of the 2-fluoro substituent. When the aryl-
ation of oxime 5 with benzonitrile 14b was conducted
without the use of 18-crown-6, the ratio of 15b and 16b
was not significantly altered.
a
(a) KH, 18-crown-6 (4 mol %), THF, 0 °C, 86%. (b) Conditions:
see Table 1. (c) Pd/C, H2, THF, 42 psi, rt 2 h, 76%. (d) 4-Fluo-
robenzoyl chloride, Et3N, rt 12 h, 77%.
Next, efforts were focused on the selective incorpora-
tion of fluorine atoms into the aromatic portion of the
tetrahydrodibenzofuran ring system. The synthesis of
fluorinated tetrahydrodibenzofurans has not been de-
scribed in the literature. Analogous routes, as described
above, starting from the appropriate commercially avail-
able fluorobenzene derivatives were explored for their
preparation.
For the preparation of the 6-fluoro-tetrahydrodiben-
zofuran analogue 13, condensation of oxime 5 with 1,2-
difluoro-4-nitrobenzene (10) provided O-aryloxime 11 in
good yield (Scheme 2). The acid-catalyzed cyclization of
11, which contains an electron-withdrawing fluoro sub-
stituent ortho to the oxygen of the oxime, was anticipated
to require much more vigorous conditions when compared
with the cyclization of desfluoro derivative 6. Addition-
ally, electronic dipole effects due to the o-fluorine sub-
stituent may destabilize the required conformation for
[3,3]-sigmatropic rearrangement. In the related acid-
catalyzed Fischer indole reaction, electron-withdrawing
substituents have been shown to reduce the rate of
cyclization.14 Also, byproducts derived from [3,3]-sigma-
tropic rearrangement to the substituted side of the
aromatic ring have been observed in the Fischer indole
reaction. In a study of the [3,3]-sigmatropic rearrange-
ment of aryloximes to benzofuran derivatives, byproducts
derived from cyclization onto an ortho tosyloxy group
were reported.7g
Various conditions for the cyclization of 11 were
explored (Table 1). Refluxing 1 M hydrogen chloride in
Since our synthesis required the para regioisomer
15a -c, we looked for more regioselective conditions for
(12) Mukai, C.; Nomura, I.; Kataoka, O.; Hanaoka, M. Synthesis
1999, 1872.
(13) Flaugh, M. E.; Mullen, D. L.; Fuller, R. W.; Mason, N. R. J .
Med. Chem. 1988, 31, 1746.
(14) For a review of the Fischer Indole reaction see: Hughes, D. L.
Org. Prep. Proc. Int. 1993, 25, 607.
(15) Wells, K. M.; Shi, Y.-J .; Lynch, J . E.; Humphrey, G. R.; Volante,
R. P.; Reider, P. J . Tetrahedron Lett. 1996, 37, 6439.
772 J . Org. Chem., Vol. 68, No. 3, 2003

[3,3]-Sigmatropic Rearrangement of O-Aryloximes
SCHEME 3a
observed in these experiments. A large boost in selectivity
was observed when the arylation was conducted by
utilizing phase-transfer conditions with tetrabutylam-
monium sulfate as catalyst. These conditions resulted in
a significantly improved 85:15 ratio of 15c and 16c in
favor of substitution at the 4-fluoro substituent. The
desired O-aryloxime 15c was isolated in 38% yield after
silica gel chromatography. Phase-transfer-catalyzed nu-
cleophilic aromatic substitution reactions of various
fluorinated benzene derivatives have been described, but
the effect of phase transfer conditions versus other
conditions on regioselectivity was not described.16 Sub-
stitution at the 2-fluoro position of 14c, adjacent to the
lipophilic tert-butyl ester, may be disfavored due to steric
repulsion with the large lipophilic tetrabutylammonium
counterion that is associated with the oxime anion.
The structures of 15a -c and 16a -c were assigned on
the basis of the coupling constants in their corresponding
1H NMR spectra. For 15a -c, Ha (see Scheme 3) was
observed as a dd, whereas for 16a -c, Ha was observed
as a ddd, consistent with what would be expected.
Cyclization of 15c with saturated, anhydrous HCl in
acetic acid again required elevated temperature of 120
°C in a sealed flask to give a 1:1.5 ratio of regioisomers
17 and 18. A regioisomeric mixture of products was
anticipated on the basis of related literature for forming
benzofuran and indole derivatives.7g,14 Convenient sepa-
ration of the two regioisomeric carboxylic acids 17 and
18 could not be achieved.
Curtius rearrangement on the mixture of carboxylic
acids 17 and 18 in tert-butyl alcohol provided the corre-
sponding tert-butylcarbamates; these intermediates were
converted to amines 19 and 20 after treatment with TFA.
At this stage the regioisomers 19 and 20 were separable
by chromatography on silica gel. The structures of 19 and
20 were assigned on the basis of the coupling constants
1
in their H NMR spectra. Separate conversion of amines
19 and 20 to the amides 21 and 22 proceeded under
standard conditions.
a
(a) Conditions: see Table 2. (b) sat. anhyd HCl in HOAc, sealed
The preparation of the 6,9-difluorinated tetrahydro-
dibenzofuran scaffold started with the conversion of 2,4,5-
trifluorobenzoic acid (23a ) to tert-butyl ester 23b (Scheme
4). Arylation of tert-butyl ester 23b with oxime 5 under
phase-transfer conditions led to the selective formation
of the 4-substituted aryloxime 24; none of the corre-
sponding regioisomer derived from substitution of the
2-fluoro substituent was observed. The inductive effect
of the 5-fluoro substituent apparently helps to direct the
alkylation to the 4-position of benzoate 23b. Analysis of
the 19F NMR spectrum of 24 gave a coupling constant of
15.2 Hz, typical of p-F’s in a substituted aromatic ring.17
flask, 120 °C 2 h, 70%, 17 + 18 (1:1.5 ratio). (c) (PhO)2P(O)N3,
Et3N, t-BuOH, reflux 24 h, 47%. (d) TFA, chromatographic
separation of regioisomers, 19, 31%; 20, 34%. (e) 4-Fluorobenzoyl
chloride, Et3N, rt 6 h, 21, 60%; 22, 80%.
TABLE 2. Rea ction Con d ition s for th e Con ver sion of
14a -c to 15a -c a n d 16a -c
starting
r a tio
entry material
conditions
15:16
1
2
3
4
14a
14b
14c
14c
KH, 18-crown-6 (cat.), THF
KH, 18-crown-6 (cat.), THF
KH, 18-crown-6 (cat.), THF
3:97
35:65
55:45
Bu4NHSO4, tol/50% aq NaOH, rt 2 h 85:15
(38%, 15c)
Cyclization of 24 with saturated, anhydrous HCl in
acetic acid at 135 °C in a sealed flask followed by
reesterification with methanol led to 25 in moderate
yields. The inductive electron-withdrawing effect of two
fluoro substituents apparently further diminished the
cyclization yield when compared with the monofluoro and
desfluoro derivatives. Attempts to cyclize 24 using alter-
its preparation. Arylation of oxime 5 with tert-butyl 2,4-
difluorobenzoate (14c) using the reaction conditions of
KH and 18-crown-6 provided a 55:45 ratio of 15c and 16c.
Presumably, the more sterically hindered tert-butyl ester
provided additional selectivity for substitution of the
4-fluoro substituent. In attempts to optimize this reaction
further, a number of reaction conditions were explored
where the temperature, solvent, and counterion were
independently varied; however, no significant changes in
the ratio of the arylation products 15c and 16c were
(16) Marriott, J . H.; Moreno Barber, A. M.; Hardcastle, I. R.;
Rowlands, M. G.; Grimshaw, R. M.; Neidle, S.; J arman, M. J . Chem.
Soc., Perkin Trans. 1 2000, 2465 and references contained therein.
(17) Paudler, W. W. Nuclear Magnetic Resonance General Concepts
and Applications; J ohn Wiley & Sons: New York, 1987.
J . Org. Chem, Vol. 68, No. 3, 2003 773

Guzzo et al.
SCHEME 4a
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. 1H
NMR spectra were recorded at 300 MHz. 19F NMR spectra
were recorded at 282 MHz. Elemental analyses were per-
formed at Quantitative Technologies Inc. (Whitehouse, NJ ).
HPLC analyses were performed on a Waters Symmetry C18
reverse phase column (4.6 × 250 mm, flow rate 1 mL/min,
detection at 254 nm) using the following gradient elution: 95:5
H2O/CH3CN + 0.1% TFA for 5 min and then a linear gradient
elution to 0:100 H2O/CH3CN + 0.1% TFA over 20 min. All
reactions were performed under a dry N2 atmosphere. Analyti-
cal TLC was performed on silica gel GF (Analtech) or silica
gel 60 F254 (EM Science) plates. Flash column chromatography
was performed with silica gel 60 (230-400 mesh, EM Science).
4-Dim eth yla m in ocycloh exa n on e Oxim e (5). Ketone 4
(200 g, 1.28 mol) was dissolved in methylene chloride (900 mL),
after which glacial acetic acid (7.33 mL, 0.128 mol) and a 2 M
solution of dimethylamine in tetrahydrofuran (800 mL, 1.60
mol) was added. The reaction was cooled to less than 10 °C,
after which sodium triacetoxyborohydride (100 g, 0.47 mol) was
slowly added. After 25 min, additional sodium triacetoxyboro-
hydride (290 g, 1.37 mol) was added. The reaction was allowed
to stir while warming to room temperature overnight, after
which it was cooled in an ice water bath. Water (1.5 L) was
added, and the reaction was adjusted to pH 9 with solid
potassium carbonate. The aqueous layer was extracted with
chloroform (5 × 1 L), and the combined organic extracts were
dried over magnesium sulfate, filtered, and evaporated under
reduced pressure to afford the intermediate ketal as a dark
1
green oil: Rf 0.25 (89:10:1 CH2Cl2/MeOH/NH4OH); H NMR
(CDCl3) δ 1.60 (m, 4H), 1.83 (m, 4H), 2.37 (s, 6H), 2.48 (m,
1H), 3.94 (s, 4H). The crude ketal was diluted with water (100
mL), and 6 M hydrochloric acid (1200 mL) was added slowly
over 30 min. The reaction was heated to reflux for 1 h, after
which it was cooled in an ice bath. Solid potassium carbonate
was slowly added to adjust the pH to 10. A white solid
appeared, which was filtered off and discarded. The reaction
was then extracted with chloroform (10 × 500 mL), and the
combined organic layers were dried over magnesium sulfate,
filtered, and evaporated under reduced pressure to afford a
red-brown oil. Distillation under reduced pressure (0.5 mmHg,
48 °C) afforded 4-dimethylaminocyclohexanone as a colorless
oil (119 g, 66% over two steps): Rf 0.25 (89:10:1 CH2Cl2/MeOH/
a
(a) t-BuOH, Boc2O, DMAP, 30 °C 24 h, 70%. (b) 5, Bu4NHSO4,
toluene/NaOH (50% w/w aq), rt 1 h, 64%. (c) (i) sat. anhyd HCl in
HOAc, 135 °C, sealed flask, 1 h. (ii) MeOH, pTSA (1.2 equiv), reflux
36 h, 20%. (d) 2 M NaOH, MeOH/H2O (10:1), rt 12 h; 2 N HCl,
83%. (e) (PhO)2P(O)N3, Et3N, t-BuOH, reflux 7 h, 26%. (f) HCl,
MeOH, 0 °C to rt, 80%. (g) 4-Fluorobenzoyl chloride, Et3N, rt 12
h, 66%.
1
native conditions including anhydrous HCl in ethanol,
10% H2SO4 in ethanol, concentrated aqueous HCl, and
10% trifluoroacetic acid in toluene resulted in no im-
provement in yield. Conversion of the initially formed
carboxylic acid to methyl ester 25 was required for the
efficient purification. Subsequent hydrolysis of 25 to
carboxylic acid 26 proceeded efficiently. Curtius rear-
rangement of 26 to form the tert-butylcarbamate followed
by treatment with HCl provided amine 27. Transforma-
tion of amine 27 to amide 28 proceeded smoothly.
NH4OH); H NMR (CDCl3) δ 1.85 (m, 4H), 2.05 (m, 4H), 2.33
(s, 6H), 2.49 (m, 1H). To a solution of 4-dimethylaminocyclo-
hexanone (119 g, 840 mmol) in anhydrous ethanol (1.6 L) was
added hydroxylamine hydrochloride (52.6 g, 756 mmol). After
vigorous stirring, anhydrous pyridine (229 mL, 2.84 mol) was
added. The reaction was heated to reflux for 3 h, after which
the reaction was allowed to cool to room temperature while
stirred overnight. The reaction was then evaporated under
reduced pressure to give a pale green solid, which was
subjected to high vacuum at 50 °C for 1 h. The solid was then
dissolved in water (350 mL) and washed with methylene
chloride (2 × 200 mL). The organic extracts were then
discarded. The aqueous layer was then adjusted to pH 10 with
solid potassium carbonate and extracted with chloroform (9
× 800 mL). The combined organic layers were dried over
magnesium sulfate, filtered, and evaporated under reduced
pressure to afford 5 as a white solid (115 g, 87%): mp 77-80
°C; Rf 0.20 (90:10:0.5 CH2Cl2/MeOH/NH4OH); 1H NMR (CDCl3)
δ 1.51 (m, 2H), 1.85-2.06 (m, 3H), 2.11 (m, 1H), 2.29 (s, 6H),
2.43 (m, 2H), 3.20 (m, 1H), 7.19 (s, 1H); APCI MS m/z 157 [M
+ H]+. Anal. Calcd for C8H16N2O: C, 61.51; H, 10.32; N, 17.93.
Found: C, 61.22; H, 10.34; N, 17.97.
In conclusion, a unified synthetic strategy was devel-
oped to prepare 8-amido-2-(dimethylamino)-1,2,3,4-tet-
rahydro-2-dibenzofurans and several aryl ring fluorinated
analogues. To enable this strategy, conditions were
developed to prepare the requisite intermediate O-
aryloximes through a regioselective addition of oxime 5
to various fluorinated benzene compounds containing
appropriate electron-withdrawing groups. Modified acidic
conditions were developed to allow cyclization of the
fluorinated O-aryloximes through a [3,3]-sigmatropic
rearrangement to the desired tetrahydrodibenzofuran
intermediates. These intermediates were then elaborated
to 8-amido-2-(dimethylamino)tetrahydrodibenzofurans
for biological testing.
4-Dim et h yla m in ocycloh exa n on e O-(4-Nit r op h en yl)-
oxim e (6). A suspension of potassium hydride (3.24 g, 28.3
mmol, 35% in mineral oil, prewashed with hexanes) in THF
(60 mL) was cooled to 0 °C and a solution of 5 (3.99 g, 25.5
mmol) in THF (20 mL) was added over 5 min. After the
reaction temperature was maintained at 0 °C for 1 h, 1-fluoro-
4-nitrobenzene (4.00 g, 28.3 mmol) and 18-crown-6 (0.224 g,
774 J . Org. Chem., Vol. 68, No. 3, 2003

[3,3]-Sigmatropic Rearrangement of O-Aryloximes
0.849 mmol) were added. After 1 h, the ice was removed and
the reaction was left to slowly warm to room temperature.
After stirring for 2 h, the reaction was quenched with
saturated aqueous sodium chloride (60 mL). The aqueous layer
was extracted with chloroform (3 × 150 mL). The combined
organic extracts were dried over magnesium sulfate, filtered,
and concentrated. The residue was purified by silica gel column
chromatography eluting with CH2Cl2/MeOH/NH4OH (95:5:0.5)
to afford 6 (6.35 g, 90%) as an off-white solid: mp 60-63 °C;
Calcd for C21H21FN2O2: C, 71.57; H, 6.01; N, 7.95; F, 5.39.
Found: C, 71.36; H, 5.86; N, 7.72; F, 5.25.
4-Dim eth yla m in ocycloh exa n on e O-(2-F lu or o-4-n itr o-
p h en yl)oxim e (11). A suspension of potassium hydride (8.06
g, 70.4 mmol, 35% in mineral oil, prewashed with hexanes) in
THF (4 mL) was cooled to 0 °C and a solution of 5 (10.0 g,
64.0 mmol) in THF (400 mL) was added over 10 min. After
the reaction temperature was maintained at 0 °C for 1.5 h,
1,2-difluoro-4-nitrobenzene (7.8 mL, 70 mmol) and 18-crown-6
(0.628 g, 2.38 mmol) were added. After 30 min, the ice was
removed and the reaction was left to slowly warm to room
temperature. After stirring for 2 h, the reaction was quenched
with saturated aqueous sodium chloride (300 mL). The organic
layer was concentrated and redissolved in methylene chloride
(300 mL). The aqueous layer was extracted with methylene
chloride (4 × 200 mL). The combined organic extracts were
washed with water (300 mL), dried over potassium carbonate,
filtered, and concentrated. The residue was purified by silica
gel column chromatography eluting with CH2Cl2/MeOH/NH4-
OH (96:4:1) to afford 11 (16.3 g, 86%) as an off-white solid:
mp 60-62 °C; Rf 0.24 (95:5:0.5 CH2Cl2/MeOH/ NH4OH); 1H
NMR (DMSO-d6) δ 1.52 (m, 2H), 1.92 (m, 2H), 2.20 (s, 6H),
2.30-2.60 (m, 4H), 3.12 (m, 1H), 7.69 (t, J ) 8.7 Hz, 1H), 8.14
(dd, J ) 2.4, 8.6 Hz, 1H), 8.23 (dd, J ) 2.4, 10.9 Hz, 1H); CI
1
Rf 0.27 (95:5:0.5 CH2Cl2/MeOH/NH4OH); H NMR (CDCl3) δ
1.64 (m, 2H), 2.02 (m, 2H), 2.15-2.35 (m, 2H), 2.31 (s, 6H),
2.48 (m, 1H), 2.67 (m, 1H), 3.28 (m, 1H), 7.25 (d, J ) 9.3 Hz,
2H), 8.20 (d, J ) 9.3 Hz, 2H); APCI MS m/z 278 [M + H]+.
Anal. Calcd for C14H19N3O3: C, 60.64; H, 6.91; N, 15.15.
Found: C, 60.35; H, 6.96; N, 14.79.
Dim et h yl(8-n it r o-1,2,3,4-t et r a h yd r od ib en zofu r a n -2-
yl)a m in e (7). A mixture of 6 (1.50 g, 5.41 mmol) in 1.0 M HCl
in acetic acid (20 mL) was heated to 90 °C for 2.5 h. To the
reaction mixture was added 1.0 M HCl in acetic acid (10 mL)
and the temperature was increased to 110 °C. After 5 h the
reaction mixture was cooled to room temperature and the
excess solvent removed under reduced pressure. Water (40 mL)
was added and the resulting solution was basified with 10%
aqueous potassium carbonate to pH 10 (pH paper). The
aqueous layer was extracted with chloroform (3 × 70 mL) and
the combined organic layers were dried over magnesium
sulfate, filtered, and evaporated. The residue was purified by
silica gel column chromatography eluting with CH2Cl2/MeOH/
NH4OH (96:4:0.5), which gave 7 (1.34 g, 95%) as an off-white
solid: mp 68-72 °C; Rf 0.54 (95:5:0.5 CH2Cl2/MeOH/NH4OH);
1H NMR (CDCl3) δ 1.86 (m, 1H), 2.25 (m, 1H), 2.41 (s, 6H),
2.64 (m, 1H), 2.74-2.96 (m, 4H), 7.44 (d, J ) 9.0 Hz, 1H), 8.14
(dd, J ) 2.3, 9.0 Hz, 1H), 8.34 (d, J ) 2.3 Hz, 1H); CI MS
(methane) m/z 261 [M + H]+. Anal. Calcd for C14H16N2O3: C,
64.60; H, 6.20; N, 10.76. Found: C, 64.21; H, 6.08; N, 10.50.
N2,N2-Dim eth yl-1,2,3,4-tetr a h yd r od iben zofu r a n -2,8-d i-
a m in e (8). To 10% palladium-on-carbon (50% wet with water,
165 mg) under a nitrogen atmosphere was added methanol
(30 mL) followed by 7 (275 mg, 1.06 mmol). The reaction
mixture was stirred under a hydrogen atmosphere (1 atm) for
12 h. The catalyst was removed by filtration through Celite
and the solution was evaporated to give the crude amine,
which was purified by silica gel column chromatography
eluting with CH2Cl2/MeOH/NH4OH (98:2:0.5), which gave 8
(209 mg, 85%) as a clear viscous oil: Rf 0.25 (80:10:0.5 CH2-
Cl2/MeOH/NH4OH); 1H NMR (CDCl3) δ 1.79 (m, 1H), 2.16 (m,
1H), 2.40 (s, 6H), 2.45-2.57 (m, 1H), 2.69-2.90 (m, 4H), 3.55
(br s, 2H), 6.57 (dd, J ) 2.3, 8.5 Hz, 1H), 6.70 (d, J ) 2.3 Hz,
1H), 7.17 (d, J ) 8.5 Hz, 1H); CI MS (methane) m/z 231 [M +
H]+.
MS (methane) m/z 296 [M + H]+. Anal. Calcd for C14H18
-
FN3O3: C, 56.94; H, 6.14; N, 14.23. Found: C, 57.13; H, 6.06;
N, 14.18.
(6-Flu or o-8-n itr o-1,2,3,4-tetr a h yd r od iben zofu r a n -2-yl)-
d im eth yla m in e (12). To a mixture of 11 (3.00 g, 10.1 mmol)
in acetic acid (20 mL) was added gaseous HCl until it was
saturated. The contents were closed in a sealed tube and
heated to 140 °C for 1 h. The mixture was cooled to room
temperature and evaporated. The residue was redissolved in
ethanol and evaporated twice. The residue was partitioned
between water and methylene chloride and basified with
potassium carbonate (solid) to pH 10. The layers were sepa-
rated, and the aqueous layer was extracted with methylene
chloride. The combined organic layers were dried over potas-
sium carbonate, filtered, and evaporated. The residue was
purified by silica gel column chromatography eluting with CH2-
Cl2/MeOH/NH4OH (98:2:0.5), which gave 12 (1.32 g, 47%) as
1
a solid: mp 88-90 °C; H NMR (CDCl3) δ 1.89 (m, 1H), 2.23
(m, 1H), 2.42 (s, 6H), 2.65 (m, 1H), 2.70-3.05 (m, 4H), 7.91
(dd, J ) 2.5, 10.4 Hz, 1H), 8.19 (d, J ) 2.5 Hz, 1H); APCI MS
m/z 279 [M + H]+. Anal. Calcd for C14H15FN2O3: C, 60.43; H,
5.43; N, 10.07. Found: C, 60.45; H, 5.37; N, 9.91.
Dim et h yl[8-(4-flu or ob en za m id e)-6-flu or o-1,2,3,4-t et -
r a h yd r od iben zofu r a n -2-yl]a m in e Hyd r och lor id e (13). To
10% palladium-on-carbon (622 mg) under a nitrogen atmo-
sphere was added THF (180 mL), followed by 12 (2.43 g, 8.74
mmol). The solution was shaken on a Parr apparatus with 42
psi of hydrogen for 2 h. The catalyst was removed by filtration
through and the solution was evaporated to give the crude
amine, which was dissolved in methanol and treated with
ethereal HCl, followed by evaporation to give the dihydrochlo-
ride salt (2.12 g, 76%) as an off-white solid: mp 160 °C dec; Rf
0.48 (89:10:1 CH2Cl2/MeOH/NH4OH); 1H NMR (CD3OD) δ 2.20
(m, 1H), 2.49 (m, 1H), 3.02 (s, 6H), 3.00-3.30 (m, 4H), 3.80
(m, 1H), 7.14 (dd, J ) 1.6, 10.7 Hz, 1H), 7.41 (d, J ) 1.6 Hz,
1H); HPLC Analysis >99%, tR 14.0 min; APCI MS m/z 249 [M
+ H]+. Anal. Calcd for C14H17FN2O‚1.9HCl‚1.0H2O: C, 50.11;
H, 6.28; N, 8.35; Cl, 20.07. Found: C, 49.86; H, 6.44; N, 8.08;
Cl, 20.48. To a solution of the free base (437 mg, 1.76 mmol)
in CH2Cl2 (5 mL) were added 4-fluorobenzoyl chloride (0.230
mL, 1.94 mmol) and Et3N (0.270 mL, 1.94 mmol), and the
mixture was stirred at room temperature overnight. The
reaction was concentrated under reduced pressure and the
residue was purified by silica gel column chromatography
eluting with CH2Cl2/MeOH/NH4OH (98:2:0.5), which gave the
free base of 13. The free base was dissolved in methanol,
treated with ethereal HCl, followed by evaporation to afford
13 (552 mg, 77%) as the hydrochloride salt: mp 250 °C dec;
Dim et h yl[8-(4-flu or ob en za m id e)-1,2,3,4-t et r a h yd r o-
d iben zofu r a n -2-yl]a m in e (9). Amine 8 (63 mg, 0.274 mmol)
was dissolved in tetrahydrofuran (5 mL) and to this solution
was added triethylamine (1.5 mL) followed by 4-fluorobenzoyl
chloride (0.05 mL, 0.42 mmol). After stirring for 1 h, the
volatiles were removed under reduced pressure, and the
residue was taken up in dichloromethane (5 mL) and stirred
with dilute aqueous sodium carbonate solution. After stirring
for 16 h, the dichloromethane layer was separated and the
aqueous layer extracted with fresh dichloromethane. The
dichloromethane extracts were combined, dried over sodium
sulfate, and concentrated under reduced pressure. The residue
was subjected to silica gel column chromatography eluting with
CHCl3/MeOH/NH4OH (95:5:0.25). Fractions containing product
were combined and concentrated under reduced pressure. The
resulting residue was crystallized from toluene/hexane to
provide 9 (58 mg, 60%) as a crystalline solid in two crops: mp
137-138 °C; Rf 0.49 (90:10:0.5 CH2Cl2/MeOH/NH4OH); 1H
NMR (CD3OD) δ 2.18 (m, 1H), 2.46 (m, 1H), 2.90-3.08 (m,
3H), 3.02 (s, 6H), 3.20 (m, 1H), 3.77 (m, 1H), 7.25 (m, 2H),
7.39 (m, 2H), 8.00 (m, 3H); APCI MS m/z 353 [M + H]+. Anal.
J . Org. Chem, Vol. 68, No. 3, 2003 775

Guzzo et al.
Rf 0.69 (89:10:1 CH2Cl2/MeOH/NH4OH); 1H NMR (DMSO-d6)
δ 2.05 (m, 1H), 2.45 (m, 1H), 2.84 (s, 6H), 2.80-3.00 (m, 3H),
3.13 (m, 1H), 3.70 (m, 1H), 7.39 (t, J ) 8.7 Hz, 2H), 7.59 (d, J
) 13.3 Hz, 1H), 7.93 (s, 1H), 8.07 (dd, J ) 5.5, 8.6 Hz, 2H),
10.49 (s, 1H), 10.96 (br s, 1H); HPLC Analysis >99%, tR 17.9
min; APCI MS m/z 371 [M + H]+. Anal. Calcd for C21H20F2N2O2‚
1.0HCl‚0.5H2O: C, 60.65; H, 5.33; N, 6.74; Cl, 8.53. Found:
C, 60.69; H, 5.26; N, 6.68; Cl, 8.76.
4-Dim eth yla m in ocycloh exa n on e O-(3-F lu or o-4-n itr o-
p h en yl)oxim e (15a ) a n d 4-Dim eth yla m in ocycloh exa n on e
O-(5-F lu or o-2-n itr op h en yl)oxim e (16a ). Using the same
reaction conditions as described for the preparation of 6, an
inseparable mixture of 15a and 16a (88%) in a ratio of 3:97
was obtained. Characterization data for 15a : 1H NMR (CDCl3)
δ 1.55-1.71 (m, 3H), 1.95-2.08 (m, 2H), 2.16-2.38 (m, 7H),
2.46 (m, 1H), 2.65 (m, 1H), 3.24, (m, 1H), 6.98 (ddd, J ) 1.1,
2.4, 9.3 Hz, 1H), 7.14 (dd, J ) 2.5, 13.0 Hz, 1H), 8.13 (m, 1H).
Characterization data for 16a : 1H NMR (CDCl3) δ 1.55-1.71
(m, 3H), 1.95-2.08 (m, 2H), 2.16-2.38 (m, 7H), 2.46 (m, 1H),
2.65 (m, 1H), 3.39 (m, 1H), 6.73 (ddd, J ) 2.7, 7.2, 9.2 Hz,
1H), 7.51 (dd, J ) 2.7, 10.8 Hz, 1H), 8.05 (dd, J ) 5.9, 9.2 Hz,
1H). Inseparable mixture of 15a and 16a : Rf 0.46 (90:10:0.5
CH2Cl2/MeOH/NH4OH); CIMS (methane) m/z 296 [M + H]+.
Anal. Calcd for C14H18FN3O3‚0.15H2O: C, 56.28; H, 6.05; N,
13.99. Found: C, 56.42; H, 6.19; N, 14.10.
(m, 1H), 2.66 (m, 1H), 3.45 (m, 1H), 6.65 (ddd, J ) 2.6, 7.7,
8.7 Hz, 1H), 7.32 (dd, J ) 2.6, 11.4 Hz, 1H), 7.78 (dd, J ) 6.7,
8.7 Hz, 1H). Partially separable mixture of 15c and 16c: Rf
0.22 (95:5:0.5 CH2Cl2/MeOH/NH4OH); APCI MS m/z 351 [M
+ H]+. Anal. Calcd for C19H27FN2O3: C, 65.12; H, 7.77; N, 7.99.
Found: C, 65.02; H, 7.81; N, 7.86.
Dim eth yl(9-flu or o-8-ca r boxy-1,2,3,4-tetr a h yd r od iben -
zofu r a n -2-yl)a m in e Hyd r och lor id e (17) a n d Dim et h yl-
(7-flu or o-8-ca r b oxy-1,2,3,4-t et r a h yd r od ib en zofu r a n -2-
yl)a m in e Hyd r och lor id e (18). To a solution of 1 M HCl in
acetic acid (7.5 mL) at 0 °C was added 15c (1.00 g, 2.85 mmol),
which formed a precipitate. The mixture was warmed to room
temperature to give a solution. HCl(g) was bubbled through
the solution for 3 min until saturated. The solution was sealed
in a pressure tube and heated to 120 °C for 2 h. The mixture
was cooled in an ice bath, and hexanes were added. The
resultant precipitate was isolated by filtration and recrystal-
lized from methanol to give a white solid. The mother liquor
was treated with ether to obtain a second crop. The combined
crops were dried under vacuum to give a 1.5:1 mixture of 18
and 17 (630 mg, 70%) as the hydrochloride salts in the form
of an off-white solid: 1H NMR (CD3OD) δ 2.19 (m, 1H), 2.20-
2.30 (s, 1H), 2.43 (s, 1H), 2.66 (m, 1H), 3.01 (s, 6H), 2.92-3.10
(m, 3H), 3.79 (m, 1H), 7.31 (m, 1H), 7.85 (m, 0.4H), 8.09 (d, J
) 7.1 Hz, 0.6H); MS m/z 278 [M + H]+.
4-(4-Dim eth yla m in ocycloh exylid en ea m in ooxy)-2-flu o-
r oben zon itr ile (15b) a n d 2-(4-Dim eth yla m in ocycloh exyl-
id en ea m in ooxy)-4-flu or oben zon itr ile (16b). Using the
same reaction conditions as described for the preparation of
6, an inseparable mixture of 15b and 16b (54%) in a ratio of
35:65 was obtained. Characterization data for 15b: 1H NMR
(CDCl3) δ 1.56-1.71 (m, 3H), 1.94-2.09 (m, 2H), 2.14-2.31
(m, 7H), 2.45 (m, 1H), 2.64 (m, 1H), 3.24 (m, 1H), 6.98 (dd, J
) 1.7, 8.7 Hz, 1H), 7.10 (dd, J ) 2.2, 11.1 Hz, 1H), 7.50 (dd, J
) 7.3, 8.7 Hz, 1H). Characterization data for 16b: 1H NMR
(CDCl3) δ 1.56-1.71 (m, 3H), 1.94-2.09 (m, 2H), 2.14-2.31
(m, 7H), 2.45 (m, 1H), 2.64 (m, 1H), 3.36 (m, 1H), 6.73 (ddd, J
) 2.5, 7.9, 8.6 Hz, 1H), 7.32 (dd, J ) 2.4, 10.8 Hz, 1H), 7.52
(dd, J ) 6.0, 8.6 Hz, 1H). Inseparable mixture of 15b and
16b: Rf 0.49 (90:10:0.5 CH2Cl2/MeOH/NH4OH); CIMS (meth-
ane) m/z 276 [M + H]+. Anal. Calcd for C15H18FN3O‚0.1H2O:
C, 65.00; H, 6.44; N, 15.10. Found: C, 65.01; H, 6.62; N, 15.16.
4-(4-Dim eth yla m in ocycloh exylid en ea m in ooxy)-2-flu o-
r oben zoic Acid ter t-Bu tyl Ester (15c) a n d 2-(4-Dim eth yl-
a m in ocycloh exylid en ea m in ooxy)-4-flu or oben zoic Acid
ter t-Bu tyl Ester (16c). To a solution of tert-butyl alcohol (300
mL) were added 2,4-difluorobenzoic acid (10.0 g, 63.3 mmol),
di-tert-butyl dicarbonate (27.6 g, 126 mmol), and 4-(dimethyl-
amino)pyridine (2.30 g, 18.9 mmol). The solution was stirred
for 48 h, diluted with ethyl acetate (750 mL), and washed with
1 M HCl (2 × 250 mL) and saturated sodium bicarbonate (2
× 250 mL). The organic layer was dried over sodium sulfate,
filtered, and evaporated to give the tert-butyl 2,4-difluoroben-
zoate (11.6 g, 86%): 1H NMR (CDCl3) δ 1.58 (s, 9H), 6.80-
6.92 (m, 2H), 7.89 (dd, J ) 8.4, 15.1 Hz, 1H). To a well-stirred
solution of the tert-butyl 2,4-difluorobenzoate (31.0 g, 144
mmol) in toluene (960 mL) were sequentially added tetrabu-
tylammonium hydrogen sulfate (12 g, 58 mmol), 5 (15 g, 96
mmol), and 50% aqueous NaOH (385 mL). The solution was
stirred for 2 h and then poured into water (1 L) and extracted
with ethyl acetate (500 mL). The aqueous layer was extracted
with chloroform (2 × 750 mL). The combined organic extracts
were washed with water (750 mL), dried over sodium sulfate,
and concentrated to give a 85:15 mixture of 15c and 16c. The
mixture was purified by medium-pressure silica gel chroma-
tography using a gradient elution of CH2Cl2/MeOH/Et3N (98:
1:1 to 95:4:1), which gave 12.8 g (38%) of the desired isomer
15c: 1H NMR (CDCl3) δ 1.58 (s, 9H), 1.91-2.08 (m, 2H), 2.10-
2.36 (m, 4H), 2.31 (s, 6H), 2.47 (m, 1H), 2.65 (m, 1H), 3.28 (m,
1H), 6.90 (dd, J ) 2.3, 8.7 Hz, 1H), 6.97 (dd, J ) 2.3 12.8 Hz,
1H), 7.82 (dd, J ) 8.6, 8.7 Hz, 1H). 16c: 1H NMR (CDCl3) δ
1.58 (s, 9H), 2.02 (m, 2H), 2.14-2.36 (m, 4H), 2.31 (s, 6H), 2.47
9-F lu or o-N2,N2-d im eth yl-1,2,3,4-tetr a h yd r od iben zofu -
r an -2,8-diam in e dih ydr och lor ide (19) an d 7-Flu or o-N2,N2-
d im eth yl-1,2,3,4-tetr a h yd r od iben zofu r a n -2,8-d ia m in e d i-
h yd r och lor id e (20). A mixture of 17 and 18 (1.80 g, 5.73
mmol) was dissolved in tert-butyl alcohol (18 mL) and dioxane
(18 mL). Diphenylphosphoryl azide (1.5 mL, 7.0 mmol) and
triethylamine (1.80 mL, 12.9 mmol) were added, and the
mixture was heated to reflux for 24 h. The mixture was
evaporated and purified by silica gel column chromatography
eluting with CH2Cl2/MeOH/NH4OH (95:5:1) to afford 0.926 g
(47%) of a mixture of tert-butyl carbamates: 1H NMR (CD3-
OD) δ 1.40-1.60 (m, 1H), 1.51 (s, 9H), 1.83 (m, 1H), 2.23 (m,
1H), 2.41 (s, 6H), 2.59 (m, 1H), 2.70-2.90 (m, 3H), 3.00 (m,
1H), 6.77 (t, 0.4H), 7.12-7.22 (m, 1H), 7.34 (m, 0.6H); CIMS
(methane) m/z 349 [M + H]+. To a solution of the mixture of
tert-butyl carbamates (900 mg, 2.58 mmol) in methylene
chloride (15 mL) was added trifluoroacetic acid (1.5 mL). The
solution was stirred at room temperature for 4 h and evapo-
rated. The two regioisomers were separated by silica gel
chromatography, eluting with CH2Cl2/MeOH/NH4OH (95:5:1),
to give the free bases of 19 (200 mg, 31%) and 20 (220 mg,
34%). The dihydrochloride salts were prepared by dissolving
the free bases in methanol and treating with ethereal HCl,
followed by evaporation. 19: mp 267-272 °C; Rf 0.53 (90:10:1
1
CH2Cl2/CH3OH/ NH4OH); H NMR (CD3OD) δ 2.17 (m, 1H),
2.48 (m, 1H), 3.01 (s, 6H), 3.00-3.17 (m, 3H), 3.30-3.40 (m,
1H), 3.81 (m, 1H), 7.33 (dd, J ) 7.5, 8.7 Hz, 1H), 7.44 (d, J )
8.7 Hz, 1H); HPLC Analysis 98.8%, tR 11.6 min; APCI MS m/z
249 [M + H]+. Anal. Calcd for C14H17FN2O‚1.95HCl‚0.6H2O:
C, 50.79; H, 6.16; N, 8.46; Cl, 20.88. Found: C, 50.99; H, 6.40;
N, 7.87; Cl, 20.73. 20: mp 238-240 °C; Rf 0.41 (90:10:1 CH2-
Cl2/CH3OH/NH4OH);1H NMR (CD3OD) δ 2.17 (m, 1H), 2.40
(m, 1H), 3.01 (s, 6H), 2.90-3.40 (m, 4H), 3.75 (m, 1H), 7.35
(d, J ) 7.9 Hz, 1H), 7.42 (d, J ) 10.5 Hz, 1H); HPLC Analysis
>99%, tR 12.5 min; CIMS (methane) m/z 249 [M + H]+. Anal.
Calcd for C14H17FN2O‚1.7HCl‚0.75H2O: C, 51.93; H, 6.29; N,
8.65; Cl, 18.61. Found: C, 51.73; H, 6.09; N, 8.32; Cl, 18.33.
Dim et h yl[8-(4-flu or ob en za m id e)-9-flu or o-1,2,3,4-t et -
r a h yd r od iben zofu r a n -2-yl]a m in e Hyd r och lor id e (21). To
a solution of free base 19 (52 mg, 0.21 mmol) in methylene
chloride (1.5 mL) were added 4-fluorobenzoyl chloride (32 µL,
0.27 mmol) and triethylamine (40 µL, 0.29 mmol). The solution
was stirred for 5.5 h at room temperature, diluted with
methylene chloride (50 mL), and washed with 10% K2CO3 (50
mL). The aqueous layer was extracted with methylene chloride
(3 × 25 mL). The combined organic layers were dried over
sodium sulfate, filtered, and evaporated. The solid was recrys-
776 J . Org. Chem., Vol. 68, No. 3, 2003

[3,3]-Sigmatropic Rearrangement of O-Aryloximes
tallized from methylene chloride and diethyl ether. The
resulting solid was dissolved in methanol, the solution was
clarified by filtration, and then 2 M HCl in ether was added
with stirring. The reaction was filtered and the white solid
was dried under vacuum at 76 °C overnight to give 47 mg
(60%) of free base 21. The free base was dissolved in methanol,
treated with ethereal HCl, followed by evaporation to afford
hydrochloride salt 21: mp 155-160 °C dec; Rf 0.41 (90:10:0.5
CH2Cl2/CH3OH/NH4OH);1H NMR (CD3OD) δ 2.16 (m, 1H),
2.42 (m, 1H), 3.01 (s, 6H), 3.00-3.14 (m, 2H), 3.30-3.40 (m,
2H), 3.79 (m, 1H), 7.23-7.37 (m, 4H), 8.03 (dd, J ) 5.3, 8.5
Hz, 2H); HPLC Analysis >99%, tR 19.9 min; APCI MS m/z 371
[M + H]+. Anal. Calcd for C21H20F2N2O2‚1.1HCl‚1.6H2O: C,
57.41; H, 5.57; N, 6.38; Cl, 8.88. Found: C, 57.17; H, 5.61; N,
6.24; Cl, 9.11.
Dim et h yl[8-(4-flu or ob en za m id e)-7-flu or o-1,2,3,4-t et -
r a h yd r od iben zofu r a n -2-yl]a m in e Hyd r och lor id e (22).
The title compound was prepared from free base 20 (60 mg,
0.242 mmol), 4-fluorobenzoyl chloride (32 µL, 0.27 mmol), and
triethylamine (40 µL, 0.29 mmol) in methylene chloride (1.5
mL) to give free base 22 as a white solid (71 mg, 80%) using
a method substantially equivalent to that described for 21. The
free base was dissolved in methanol, treated with ethereal HCl,
followed by evaporation to afford hydrochloride salt 22: mp
250 °C dec; Rf 0.43 (90:10:0.5 CH2Cl2/CH3OH/NH4OH); 1H
NMR (CD3OD) δ 2.16 (m, 1H), 2.41 (m, 1H), 3.01 (s, 6H), 3.00-
3.40 (m, 4H), 3.77 (m, 1H), 7.27 (t, J ) 8.6 Hz, 2H), 7.39 (d, J
) 9.9 Hz, 1H), 7.80 (d, J ) 7.4 Hz, 1H), 8.04 (dd, J ) 5.4, 8.5
Hz, 2H); HPLC Analysis 97.9%, tR 20.4 min; APCI MS m/z
371 [M + H]+. Anal. Calcd for C21H20F2N2O2‚1.1HCl‚1.0H2O:
C, 58.86; H, 5.43; N, 6.54; Cl, 9.10. Found: C, 58.98; H, 5.47;
N, 6.49; Cl, 9.47.
4-(4-Dim eth yla m in ocycloh exylid en ea m in ooxy)-2,5-d i-
flu or oben zoic Acid ter t-Bu tyl Ester (24). To a solution of
2,4,5-trifluorobenzoic acid (23a , 10.0 g, 56.8 mmol) in tert-butyl
alcohol (280 mL) were added di-tert-butyl dicarbonate (32.1 g,
114 mmol) and 4-(dimethylamino)pyridine (0.694 g, 5.68
mmol). The solution was stirred for 24 h, diluted with ethyl
acetate (600 mL), and washed with 1 N HCl (2 × 75 mL) and
saturated aqueous sodium bicarbonate (2 × 75 mL). The
organic layer was dried over sodium sulfate and filtered, and
the solvent was removed under reduced pressure. The residue
was purified by silica gel column chromatography, eluting with
hexanes/EtOAc (99:1) to afford 9.22 g (70%) of the tert-butyl
2,4,5-trifluorobenzoate (23b): Rf 0.48 (98:2 hexanes/EtOAc);
1H NMR (CDCl3) δ 1.58 (s, 9H), 6.96 (ddd, J ) 6.3, 9.9, 9.9
Hz, 1H), 7.70 (ddd, J ) 6.6, 9.0, 15.6 Hz, 1H); APCI MS, m/z
175 [M - C4H9]+. To a well-stirred solution of tetrabutylam-
monium hydrogen sulfate (2.36 g, 6.96 mmol) in 50% w/w
aqueous sodium hydroxide (70 mL) was added 5 (2.72 g, 17.4
mmol), followed by a solution of tert-butyl 2,4,5-trifluoroben-
zoate (5.66 g, 24.0 mmol) in toluene (175 mL). After stirring
for 1 h, the reaction mixture was diluted with ice-cold water
(150 mL) and toluene (150 mL). The organic layer was
separated and the aqueous layer was extracted with toluene
(150 mL). The combined organic extracts were dried over
magnesium sulfate and filtered, and the solvent was removed
under reduced pressure. The residue was purified by silica gel
column chromatography, eluting with CH2Cl2/MeOH/NH4OH
(95:5:0.5) to afford 4.09 g (64%) of oxime 24: mp 37-39 °C; Rf
0.24 (90:10:1 CH2Cl2/MeOH/NH4OH); 1H NMR (CDCl3) δ 1.45-
1.70 (m, 2H), 1.58 (s, 9H), 1.92-2.09 (m, 2H), 2.15-2.32 (m,
2H), 2.31 (s, 6H), 2.42 (m, 1H), 2.64 (m, 1H), 3.30 (m, 1H),
7.27 (dd, J ) 6.5, 12.3 Hz, 1H), 7.58 (dd, J ) 6.7, 11.5 Hz,
1H); 19F NMR (CDCl3) δ -111.90 (d, J ) 15.2 Hz, 1F), -140.96
(d, J ) 15.2 Hz, 1F); APCI MS m/z 369 [M + H]+.
acetic acid was removed under reduced pressure. Ethanol (2
× 100 mL) was added and the solvent again removed under
reduced pressure. The resulting orange solid was suspended
in a mixture of diethyl ether (50 mL) and ethanol (50 mL).
The suspension was cooled to 0 °C and the solid was collected
by filtration and dried under vacuum (50 °C) for 12 h to give
2.85 g (53%) of impure 26. The crude acid was dissolved in
methanol (100 mL) and 4-toluenesulfonic acid (2.00 g, 10.5
mmol) was added. This reaction mixture was refluxed for 36
h. After cooling to room temperature, the methanol was
removed under reduced pressure. The reaction mixture was
diluted with methylene chloride (100 mL) and water (75 mL)
and the pH adjusted to 9 with 10% aqueous potassium
carbonate. The aqueous layer was extracted with methylene
chloride (2 × 50 mL), and the combined organic extracts were
dried over sodium sulfate, filtered, and concentrated under
reduced pressure. The reaction residue was purified by silica
gel column chromatography, eluting with CH2Cl2/MeOH/NH4-
OH (97:3:0.5) to afford 1.01 g (20%) of methyl ester 25: mp
1
89-92 °C; Rf 0.46 (94:6:0.5 CH2Cl2/MeOH/NH4OH); H NMR
(CDCl3) δ 1.85 (m, 1H), 2.16 (m, 1H), 2.41 (s, 6H), 2.70-3.10
(m, 5H), 3.96 (s, 3H), 7.53 (dd, J ) 6.5, 9.5 Hz, 1H); APCI MS
m/z 310 [M + H]+. Anal. Calcd for C16H17F2NO3‚0.1H2O: C,
61.77; H, 5.57; N, 4.50. Found: C, 61.55; H, 5.35; N, 4.40.
8-Dim eth yla m in o-1,4-d iflu or o-6,7,8,9-tetr a h yd r od iben -
zofu r a n -2-ca r boxylic Acid Hyd r och lor id e (26). To a solu-
tion of methyl ester 25 (1.07 g, 3.46 mmol) in methanol/water
(10:1, 22 mL) was added 2 N NaOH (2 mL). After stirring of
the reaction overnight, the reaction mixture was acidified to
pH 0 with 2 N HCl and then cooled to 0 °C. The solid was
collected by filtration and washed with cold water (2 × 3 mL)
and acetone (3 mL). After drying of the solid under vacuum
(50 °C) for 12 h, acid 26 (949 mg, 83%) was obtained as a white
solid: mp 318-322 °C; Rf 0.18 (70:30:1.5 CH2Cl2/MeOH/ NH4-
OH); 1H NMR (DMSO-d6) δ 2.00 (m, 1H), 2.42 (m, 1H), 2.75-
3.40 (m, 4H), 2.84 (s, 6H), 3.65 (m, 1H), 7.60 (dd, J ) 6.4, 9.3
Hz, 1H), 10.90 (br s, 1H); APCI MS m/z 296 [M + H]+. Anal.
Calcd for C15H15F2NO3‚1.0HCl‚0.7H2O: C, 52.32; H, 5.09; N,
4.07; Cl, 10.30. Found: C, 52.24; H, 4.71; N, 4.00; Cl, 10.55.
6,9-Diflu or o-N2,N2-d im et h yl-1,2,3,4-t et r a h yd r od ib en -
zofu r a n -2,8-d ia m in e Dih yd r och lor id e (27). Diphenylphos-
phoryl azide (0.44 mL, 2.0 mmol) was added dropwise to a
suspension of 26 (0.64 g, 1.9 mmol) and triethylamine (0.56
mL, 4.0 mmol) in tert-butyl alcohol (8 mL) and the mixture
was heated to reflux. After 7 h, the reaction was cooled to room
temperature and poured into ice water. Methylene chloride
was added and the biphasic mixture was filtered. The solid
consisted of unreacted starting material that was resubjected
to the reaction conditions. All of the combined organics were
dried over sodium sulfate, filtered, and concentrated under
reduced pressure. The crude material was purified twice on
silica gel eluting with a gradient of CH2Cl2/MeOH (98:2 to 95:
5) to afford the tert-butyl carbamate (0.18 g, 26%): 1H NMR
(CDCl3) δ 1.54 (s, 9H), 1.83 (m, 1H); 2.19 (m, 1H), 2.42 (s, 6H),
2.72-3.05 (m, 5H), 6.59 (br s, 1H), 7.76 (m, 1H); CIMS
(methane) m/z 367 [M + H]+.
A 2.0 M HCl in ether solution (9 mL) was added to a solution
of the tert-butyl carbamate (184 mg, 0.502 mmol) in MeOH (5
mL) cooled in an ice bath. After the addition was complete,
the reaction was warmed to room temperature overnight. The
reaction was concentrated under reduced pressure and the
crude material was purified by silical gel column chromatog-
raphy eluting with CH2Cl2/MeOH/NH4OH (95:5:0.5), which
afforded 108 mg (80%) of the free amine. The free amine was
further treated with ethereal HCl and concentrated under
reduced pressure to give dihydrochloride salt 27 as an off-white
solid: mp 285-288 °C dec; Rf 0.46 (95:5:0.5 CH2Cl2/MeOH/
NH4OH); 1H NMR (CD3OD) δ 2.17 (m, 1H), 2.46 (m, 1H), 3.01
(s, 6H), 2.94-3.14 (m, 3H), 3.31 (m, 1H), 3.78 (m, 1H), 6.97
(m, 1H); HPLC 97.8%, tR 13.7 min; CIMS (methane) m/z 267
[M + H]+. Anal. Calcd for C14H16F2N2O‚1.9HCl‚0.6H2O: C,
Dim eth yl(6,9-diflu or o-8-car boxym eth yl-1,2,3,4-tetr ah y-
d r od iben zofu r a n -2-yl)a m in e (25). A solution of oxime 24
(6.00 g, 16.2 mmol) in acetic acid (120 mL) was saturated with
HCl by bubbling HCl(g) through the solution for 8 min. The
solution was sealed in a pressure tube and heated to 135 °C
for 1 h. The mixture was cooled to room temperature and the
J . Org. Chem, Vol. 68, No. 3, 2003 777

Guzzo et al.
48.55; H, 5.56; N, 8.09; Cl, 19.45. Found: C, 48.90; H, 5.52;
N, 7.92; Cl, 19.11.
mixture of rotamers) δ 1.85 (m, 1H), 2.24 (m, 1H), 2.40 (s, 6H),
2.62-3.09 (m, 4H), 3.53 (m, 1H), 7.10-7.22 and 7.40-7.45 (m,
3H), 7.80-7.86 (m, 2H); HPLC 96.8%, tR 19.8 min; APCI MS
m/z 389 [M + H]+.
Dim et h yl[8-(4-flu or ob en za m id e)-7,9-d iflu or o-1,2,3,4-
tetr a h yd r od iben zofu r a n -2-yl]a m in e (28). 4-Fluorobenzoyl
chloride (0.015 mL, 0.13 mmol) was added dropwise to a
solution of free base 27 (0.030 g, 0.11 mmol) and triethylamine
(0.024 mL, 0.17 mmol) in methylene chloride (5 mL) cooled in
an ice bath. After the addition was complete, the reaction was
warmed to room temperature overnight. The reaction was
partitioned between methylene chloride and saturated aqueous
sodium bicarbonate. The layers were separated, and the
aqueous layer was extracted with methylene chloride (2 × 25
mL). The combined organics were dried over sodium sulfate,
filtered, and concentrated under reduced pressure. The crude
material was purified three times by silica gel column chro-
matography eluting with CH2Cl2/MeOH/NH4OH (95:5:0.5),
which gave 28 (0.029 g, 66%) as an off-white solid: Rf 0.66
Ack n ow led gm en t. The authors thank Drs. C. Ri-
chard King, Michael P. Trova, and Harold Meckler of
Albany Molecular Research and Dr. Warren Porter of
Eli Lilly and Co. for their insightful review of the
manuscript.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
NMR spectra for 5, 6, 7, 8, 9, 11, 12, 13, 15a /16a , 15b/16b,
14c, 15c/16c, 15c, 17/18, 19, 20, 21, 22, 23b, 24, 25, 26, 27,
28. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
(95:5:0.5 CH2Cl2/MeOH/NH4OH); H NMR (CD3OD, complex
J O020600B
778 J . Org. Chem., Vol. 68, No. 3, 2003